The AIDS epidemic in the Developing World represents a major global crisis. More than 95% of all HIV-infected people now live in the Developing World, and 95% percent of all HIV-1 related deaths have occurred among its people. Most who have died were in the prime of life, robbing their societies of their most productive workers severely taxing their infrastructures, and creating a large population of AIDS orphans. In these countries, chronic parasitic infection adds another level of complexity to AIDS vaccine development. Helminthic and protozoan infections are common in developing countries. The most conservative numbers suggest that approximately 1.5 billion people carry a parasitic burden. These persons exist in a constant state of immune activation that is characterized by a dominant Th2 type of cytokine profile, high IgE levels, and eosinophilia. Such an immune profile may have an adverse impact on the efficacy of vaccines in particular an HIV-1 vaccine. The impact of parasitic infection on vaccine effectiveness must be addressed to ensure that putative vaccines have the highest possible chance for field success. Currently there have been only a few studies of the effects of chronic parasitic infection on putative HIV-1 vaccines. The goal of my proposed project will be to study the impact of chronic parasitic infection and the resulting Th2 immune profile on an HIV-1 vaccine induced immune response. The model we will use is Leishmania major infection in Balb/c mice (there are several other excellent systems, including Schistosoma manosi, that may be used in subsequent studies). L. major infection in Balb/c mice leads to a Th2 immune profile mimicking what might be seen in the clinic in HIV-1 infected individuals. Following the establishment of chronic parasitic infection the mice will be immunized with a DNA HIV-1 vaccine (that has been reported to control viral replication and protect primates from CD4 loss). The level and quality of CD8 and CD4 responses against HIV-1 antigens will be assessed. Further, we will expand our studies to look at the effects of putative Th1 type cytokines in this model through co-administration of the HIV-1 vaccine and cytokine expressing plasmids. This proposal represents the initiation of a new and important area of research.